Auto-antibodies as predictive markers for Post treatment Lyme Disease Syndrome

自身抗体作为治疗后莱姆病综合征的预测标记

• 批准号: 10737996
• 负责人: Linden T Hu
• 金额: $ 55.52万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737996
• 关键词: Affinity; Aftercare; Animal Model; Animals; Antibiotic Therapy; Antibodies; Anticardiolipin Antibodies; Antigen-Antibody Complex; Antigens; Antiphospholipid Antibodies; Area; Arthralgia; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteria; Bacterial Proteins; Binding; Borrelia burgdorferi; Cardiolipins; Cells; Communicable Diseases; Complement Activation; Defect; Deposition; Development; Diagnostic tests; Disease; Elements; Environment; Fatigue; Fibromyalgia; Generations; Genome; Human; Hypersensitivity; Immune response; Immune system; Immunoglobulin G; Immunologic Stimulation; Infection; Injections; Laboratories; Link; Lipids; Locomotion; Long COVID; Lyme Disease; Macrophage; Membrane; Memory B-Lymphocyte; Memory Loss; Metabolic; Modeling; Mus; Myalgia; Nerve Block; Neurologic; Neurons; Nutrient; Organism; Pain; Pathogenesis; Pathogenicity; Patients; Persons; Phospholipids; Plasmin; Post Treatment Lyme Disease Syndrome; Process; Production; Reagins; Receptor Activation; Residual state; Resolution; Role; Serum; Signal Transduction; Symptoms; Synaptic Transmission; Syphilis; Testing; Theft; Time; Tissues; acute infection; autoreactivity; behavioral study; biomarker identification; brain tissue; cell injury; cost; cross reactivity; derepression; fibromyalgia patients; histological studies; lyme pathogenesis; neural; pathogenic autoantibodies; patient subsets; persistent symptom; predictive marker; response; treatment response

ABSTRACT As an organism that persists in its natural hosts for long periods of time, Borrelia burgdorferi, the causative agent of Lyme disease, has adapted many strategies for survival and evasion of host immune responses. It has a very small genome and is unable to produce many essential nutrients for itself and is instead, dependent upon utilizing them from its environment. We have recently shown that B. burgdorferi is able to acquire host phospholipids and deploy them, intact, in its membrane. A cost of utilizing host phospholipids is that it may result in production, or de-repression of autoantibodies to host phospholipid targets. Indeed, in our preliminary studies, we found that mice and humans infected with B. burgdorferi produce antibodies to host phospholipids that the organism itself does not produce. Antibodies to phospholipids arise quicker than other antibodies to B. burgdorferi and also appear to resolve more quickly, as might be expected since autoantibody production is typically tightly regulated. However, in patients with PTLDS as compared with patients who resolve their symptoms after treatment for Lyme, there appears to be increased levels of anti-phospholipid antibodies. It is unknown whether these antibodies may be pathogenic or are just a marker for PTLDS. In this proposal, we will explore the development of anti-lipid/phospholipid antibodies during Lyme disease and their potential role in PTLDS. In Aim 1, we will determine the extent of anti-lipid/phospholipid development at different stages of disease and determine their relationship to disease resolution/persistent symptoms in patients with Lyme disease. In Aim 2, we will examine binding of these antibodies to human cells and tissues and look for the presence of immune complexes which are often deposited in auto-immune diseases. Finally, in Aim 3, we will explore a new animal model for PTLDS. A recent study has shown that injection of antibodies from patients with fibromyalgia, a disease with marked similarities to PTLDS in symptoms, into mice results in hypersensitivity to pain and cold as well as changes in locomotion. Histological studies have shown binding of the human antibodies to neural tissues and macrophages. We will test a similar model using serum from patients with PTLDS, recovered Lyme disease and fibromyalgia. In our preliminary studies, we have found increased binding of antibodies from PTLDS patients to mouse brain tissue compared with binding from healthy control antibodies. The discovery of autoantibodies to lipids/phospholipids opens a new area for discovery in the pathogenesis for Lyme disease and may lead to better diagnostic tests and a new understanding of the pathogenesis of this disease.

抽象的 伯氏疏螺旋体是一种在其自然宿主中长期存在的生物体，其致病菌 莱姆病的病原体，已经采用了许多生存和逃避宿主免疫反应的策略。它 基因组非常小，无法为自身产生许多必需的营养物质，而是依赖于 从其环境中利用它们。我们最近表明，伯氏疏螺旋体能够获得宿主 磷脂并将其完整地部署在其膜中。利用宿主磷脂的一个成本是它可能 导致宿主磷脂靶标的自身抗体的产生或解除抑制。事实上，在我们的初步 研究中，我们发现感染伯氏疏螺旋体的小鼠和人类会产生针对宿主磷脂的抗体 有机体本身不产生。磷脂抗体比其他布鲁氏菌抗体产生得更快。 伯氏杆菌并且似乎也能更快地消退，正如预期的那样，因为自身抗体的产生是 通常受到严格监管。然而，与解决问题的患者相比，患有 PTLDS 的患者 莱姆病治疗后出现的症状，抗磷脂抗体水平似乎有所增加。这是 尚不清楚这些抗体是否可能具有致病性或只是 PTLDS 的标记。 在本提案中，我们将探索莱姆病和抗脂质/磷脂抗体的开发 他们在 PTLDS 中的潜在作用。在目标 1 中，我们将确定抗脂质/磷脂发展的程度 疾病的不同阶段，并确定它们与疾病消退/持续症状的关系 莱姆病患者。在目标 2 中，我们将检查这些抗体与人体细胞和组织的结合 并寻找经常沉积在自身免疫性疾病中的免疫复合物的存在。最后， 在目标 3 中，我们将探索一种新的 PTLDS 动物模型。最近的一项研究表明，注射抗体 从纤维肌痛患者（一种与 PTLDS 症状明显相似的疾病）移植到小鼠体内，结果 对疼痛和寒冷以及运动变化过敏。组织学研究表明结合 针对神经组织和巨噬细胞的人类抗体。我们将使用来自的血清测试类似的模型 患有PTLDS、已康复的莱姆病和纤维肌痛的患者。在我们的初步研究中，我们发现 与来自 PTLDS 患者的抗体与小鼠脑组织的结合相比，PTLDS 患者的抗体与小鼠脑组织的结合增加 健康对照抗体。脂质/磷脂自身抗体的发现开辟了一个新领域 莱姆病发病机制的发现可能会带来更好的诊断测试和新的方法 了解这种疾病的发病机制。